MiR-223 increases gallbladder cancer cell sensitivity to docetaxel by downregulating STMN1.

Wei Lu,Linzhu Zhou,Yingbin Liu,Lin Jiang,Weibin Shi,Qiang Ma,Zhizhen Li,Yunping Hu,Sheng Li,Shuai Zhao,Yuzhen Xu

doi:10.18632/oncotarget.11634

Abstract

BackgroundMicroRNAs (miRs) are involved in cancer carcinogenesis, and certain regulatory miRs could provide promising therapeutic methods for refractory malignancies, such as gallbladder cancer (GBC). miR-223 was found to play a pivotal role in enhancing chemotherapeutic effects, therefore evoking interest in the role of miR-223 in GBC.ResultsmiR-223 was decreased in GBC tissues and cell lines, and ectopic miR- 223 expression exhibited multiple anti-tumorigenic effects in GBC cells, including decreased proliferation, migration and invasion in vitro. However, treatment with a miR-223 inhibitor increased cell viability. We determined that STMN1 was negatively correlated with and regulated by miR-223 in GBC. miR-223 increased GBC sensitivity to docetaxel in vitro and in vivo, and the induced sensitivity to docetaxel was suppressed by the restoration of STMN1 expression.MethodsWe examined miR-223 expression in GBC tissue and GBC cell lines using qRT-PCR. The effects of modulated miR-223 expression in GBC cells were assayed using Cell Counting Kit-8 (CCK8), flow cytometry, and wound-healing and invasion assays. Susceptibility to docetaxel was evaluated in miR-223/STMN1-modulated GBC cells and xenograft tumor models. The protein expression of relevant genes was examined by Western blotting.ConclusionsThese findings indicated that miR-223 might serve as an onco-suppressor that enhances susceptibility to docetaxel by downregulating STMN1 in GBC, highlighting its promising therapeutic value.

Highlights

Gallbladder cancer (GBC) is rare; it is the most common malignancy of the biliary tract [1]
In the gallbladder cancer (GBC)-standard deviation (SD) and NOZ cell lines, quantitative real-time RTPCR (qRT-PCR) analysis showed that miR-223 expression was efficiently elevated or decreased 24 h after transfection of miR-223 mimics or miR-223 inhibitor, respectively, compared with the control group (Figure 2A)
The STMN1 mRNA and protein levels were simultaneously modulated with miR-223 mimics, miR-223 inhibitor and the STMN1 expression plasmid in GBC cells (Figure 2B–2D and Supplementary Figure S1)

Summary

Introduction

Gallbladder cancer (GBC) is rare; it is the most common malignancy of the biliary tract [1]. MicroRNAs (miRs) are noncoding 17 to 25 nucleotide RNAs that post-transcriptionally regulate gene expression [8]. These RNAs are believed to be expressed in a tissue-specific manner and play important roles in cell proliferation, apoptosis, and differentiation during mammalian development [9] as well as oncogenesis and tumor metastasis [10, 11]. Some preclinical studies have demonstrated that modulating miR expression levels could increase chemotherapy efficacy [18, 19] and have highlighted potential applications to improve the treatment of certain chemo-resistant malignancies [20]. MicroRNAs (miRs) are involved in cancer carcinogenesis, and certain regulatory miRs could provide promising therapeutic methods for refractory malignancies, such as gallbladder cancer (GBC). MicroRNAs (miRs) are involved in cancer carcinogenesis, and certain regulatory miRs could provide promising therapeutic methods for refractory malignancies, such as gallbladder cancer (GBC). miR-223 was found to play a pivotal role in enhancing chemotherapeutic effects, evoking interest in the role of miR-223 in GBC

Methods

Results

Conclusion